1-{60 -hydroxybenzyl 3-methyl, 1,2,3,4-tetrahydroiso quinolino-2-carbonitriles

ABSTRACT

Compounds are of the class of 1-aryl-3-amino-1,5,6,10btetrahydro-3H-oxazolo(4,3-a)isoquinolines, useful as central nervous system stimulants.

firmed States Patents Houiihan et a1.

[451 Aug. 28, 1973 l-a-HYDROXYBENZYL 3-METHYL, 1,2,3,4-TETRAHYDROISOQUINOLINO-Z-CARBONITRILES Inventors: William J. Houlihan; Robert E.

Manning, both of Mountain Lakes,

Assignee: Sandoz-Wander, Inc., Hanover, NJ.

Filed: Aug. 16, 1971 Appl. No.2 172,285

Related US. Application Data Division of Ser. No. 51,403, May 27, 1970,Pat. No. 3,637,709, which is a continuation-in-part of Ser. No. 663,218,Aug. 25, 1967, Pat. No. 3,565,900.

[1.8. CI 260/283 CN, 260/289 R Int. Cl C07d 35/40 Field of Search260/283 CN, 289 R,

References Cited UNITED STATES PATENTS 8/1960 Dengel 260/286 R FOREIGNPATENTS OR APPLICATIONS 694,187 7/1953 Great Britain 260/289 R OTHERPUBLICATIONS Govindachari et 211., Indian Acad. Sci, Vol. 42A, p.261-266 (1955).

Primary ExaminerDona1d G. Daus Attorney-Walter F. Jewell et a1.

Compounds are of the class of 1-ary1-3-amino-1,5,6,10b-tetrahydro-3H-oxazoio[4,3-a]isoquinolines, useful as centralnervous system stimulants.

ABSTRACT 4 Claims, N0 Drawings l-a-HYDROXYBENZYL 3-METHYL, l,2,3,4-TETRAHYDROISO QUlNOLlNO-2-CARBONITRILES This application is adivision of Ser. No. 51,403 filed May 27, 1970, now US. Pat. No.3,637,709 which in turn is a continuation-in-part of application Ser.No. 663,218 filed Aug. 25, 1967, and now US. Pat. No. 3,565,900.

This invention relates to tricyclic compounds. In particular, theinvention pertains to l-aryl-3-imino- 1,5 ,6, lb-tetrahydro-3H-oxazolo[4,3-a] isoquinolines, acid addition saltsthereof, and to processes for preparing the same. The invention alsorelates to intermediates which are useful in preparing the abovecompounds and to processes for preparing said intermediates.

The oxazolo[4,3-a]isoquinolines of the present in vention may berepresented structurally as follows:

MA/N wherein R, R, R and R, independently, represent hydrogen,trifluoromethyl, or halo having an atomic weight of about 19-36;

R and R independently, represent hydrogen, straight chain lower alkyl,or halo having an atomic weight of about 19-36; and

R represents hydrogen or straight chain lower alkyl,

provided 1. no more than three of R, R, R, R, R and R are other thanhydrogen, and

2. R, R, R and R are such that there is never a trifluoromethyl group oneach of two adjacent carbon atoms, and A is a monovalent anion.

This invention also includes within its scope the free base of thecompounds of formula (1) where R is hydrogen.

The term lower alkyl signifies an alkyl group having 1-4 carbon atoms,viz., methyl, ethyl, propyl and butyl.

The compounds of formula (1) wherein R through R are halo as definedabove represent a preferred aspect of this invention. Particularlypreferred are those com pounds where either R or R and R representchloro.

The compounds of formula (I) are conveniently prepared by reacting anappropriate a-aryl-l ,2,3,4- tetrahydroisoquinoline-l-methanol (ill)with cyanogen bromide. Alternatively, the compounds may be prepared byreacting an appropriate l-(a-hydroxybenzyl)- l ,2,3,4-tetrahydroisoquinoline-2-carboxa.mide (II) with thionyl chloride.These processes are illustrated by the following reaction scheme:

wherein R through R and A are as previously defined.

The reaction of the carboxamide (11) with thionyl chloride is carriedout in an inert organic solvent, preferably a chlorinated low molecularweight hydrocar bon, e.g., methylene chloride, chloroform and carbontetrachloride, and at an elevated temperature of from about 35C. toabout C. Preferably, the reaction is carried out at a temperature offrom about 40C. to about 50C.

Conversion of the carbinol (111) to the desired compound of formula (1)by use of cyanogen bromide is readily carried out in an inert organicsolvent and at a temperature of from about 0C. to about 20C. Preferably,the reaction is carried out at a temperature of from about 5C. to about10C. employing a lower aliphatic alcohol, e.g., methanol, ethanol andisopropanol, as the solvent. When R is straight chain lower alkyl, anintermediate tautomeric form of the free base of the compounds offormula (1) is formed having the structure It Alk N-CN R OH R1 l.

R la

where R-R are as previously defined, and such compounds are readilyconverted to the compounds of formula (l) where R is straight chainlower alkyl by treatment with acid, e.g., hydrochloric and hydrobromicacid, or sulphuric, phosphoric acid, and the like, conveniently at atemperature of from about 0C. to about 40C., preferably about roomtemperature. Use of solvent is not necessary.

In each of the above processes, the product obtained is readily isolatedemploying conventional techniques.

The free base of the compounds of formula (I) are believed to existessentially only when R is hydrogen, and such compounds may be obtainedby treating compounds (i) with a base in conventional manner.

The compounds of formula (ii) are readily obtained from thecorresponding compounds of formula (III) by treatment of the latter,under acidic conditions, with an alkali-metal isocyanate, preferablypotassium isocyamate, in an inert organic solvent, preferably a loweraliphatic alcohol, e.g., methanol, ethanol and isopropanol. The reactionis preferably carried out in the presence of a mineral acid, e.g.,hydrochloric acid, sulphuric acid and phosphoric acid, and at atemperature of from about 20C. to about 25C. However, the reaction canbe effected at a temperature of from about C. to about 35C. and in thepresence of any suitable inert inorganic or organic acid which iscapable of liberating cyanic acid, e.g., p-toluenesulfonic acid andacetic acid.

Various of the compounds of formula (iii) are known and can be preparedas described in the literature. Such others which may not bespecifically disclosed in the literature may be prepared from availablematerials in a manner analogous to that described in the literature forpreparing the known compounds. in general, such compounds are preparedby reacting l-cyano-Z- benzoyl-l ,Z-dihydroisoquinoline (prepared by theprocedure of J. Weinstock and V. Boekelheide in Organic Synthesis, Coll.Vol. 2, p. 641 with an appropriate lithium compound to form thecorresponding l-lithio derivative, treating the latter with benzaldehyde(or appropriate derivative thereof) to form the correspondinga-aryl-isoquinoline-i-methanol and catalytically hydrogenating thelatter, e.g., in acetic acid in the presence of a platinum catalyst andat a temperature of from 25 to 45C. and a hydrogen pressure of l to 5 atmospheres.

The compounds of formula (iii) are alternatively prepared fromN-(substitutedphenethyl)-2-phenyl acetamides (V) according to thefollowing reaction scheme R- I o 34 R (V) VI where R-R are as earlierdefined. These carbinol intermediates (iil) are prepared by cyclizingsaid acetamides (V) with phosphorous pentoxide in solvent such asbenzene or xylene at about to C to obtain a corresponding l-benzyldihydroisoquinoline (Vi), treating said dihydroisoquinoline with air oroxy gen, conveniently at room temperature, to obtain a correspondingl-benzoyl dihydroisoquinoline (Vii) and reducing this compound (Vii) ata temperature of 20 to 50C in solvent, e.g., ethanol, with hydrogen inthe presence of platinum as catalyst. Certain of the acetamide startingmaterials (V) are known and are prepared according to methods disclosedin the literature. Those acetamides not specifically disclosed may beprepared by analogous methods from known materials.

The compounds of formula (i) exist as geometric iso mers. Each of theabove-described processes for preparing (I) results in the production ofcompounds of a particular geometric isomer configuration. For thepurpose of this invention, the compounds (i) obtained via the reactionof the carbinols (iii) where R is hydrogen with cyanogen bromide aredesignated as isomer A while the compounds resulting from the reactionof a carboxamide (ii) where R is hydrogen with thionyl chloride aredesignated as isomer B. Likewise, reaction of the carbinols defined byformula (Ill) where R is lower alkyl with cyanogen bromide providescompounds (I) referred to herein as isomer C" whereas the compoundsresulting from the reaction of thionyl chloride with a carboxamide (ii)where R is lower alkyl may be designated as isomer D." The compounds offormula (I) in all geometric isomer forms also exist as optical isomers,and the separation and recovery of the respective isomers may be readilyaccomplished employing conventional techniques. All of the isomers(geometric and optical) are included within the scope of this invention.

All of the compounds of formula (I) are useful because they possesspharmacological activities in animals. in particular, the compoundspossess central nervous system activity and can be used asantidepressants as indicated by their activity in the mouse given 10mg/kg intraperitoneally of the active compound and tested for itsability to reverse reserpine hypothermia (Spencer, P.S.J., Antagonism ofHypothermia in the Mouse by Antidepressants, in Antidepres sant Drugs,p. 194-204, Eds., S. Garattini and M.N.G. Dukes, Excerpta MedicaFoundation, 1967).

Compounds (I) and particularly those defined as isomer B are also usefulas anorexics as indicated by their activity in rats orally given 25mg/kg of active compound and tested using the free feeding methoddescribed by Randall, et ai. (J.P.E.T., l29zl63, 1960).

For such uses, the compounds may be combined with a pharrnaceuticallyacceptable carrier, and such other conventional adjuvants, as may benecessary, and administered orally in such forms as tablets, capsules,elixirs, suspensions or solutions, or parenterally in such forms asinjectable solutions, suspensions or emulsions. The compounds may beadministered in the form of their non-toxic, pharmaceutically acceptableacid addition salts or in free base form when R is hydrogen. The saltspossess the same order of activity as said free base. The free base formof the compounds of formula (i), whether it exists as anoxazolo[4,3-a]isoquinoline or as a carbonitrile (la), is readilyprepared from the salts (i) using conventional techniques. Thepharmaceutically acceptable salts are likewise readily prepared inconventional manner by reacting the base of the compounds of formula (I)or the tautomeric intermediate la) with the appropriate acid.Representative of such salts are the mineral acid salts such as thehydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts such as the succinate, benzoate, acetate, maleate,p-toluenesulfonate and the like.

The dosage administered will, of course, vary depending on theparticular compound employed and mode of administration. However, ingeneral, satisfactory results are obtained when the compounds areadministered for the anti-depressant use at a daily dosage of from about-30 mg/kg of animal body weight, preferably given in divided doses,e.g., 2 to 4 times a day or in sustained release form. For most largemammals the total daily dosage is in the range of from about 20 mg toabout 100 mg. Suitable dosage forms comprise from about 5 mg to about 50mg admixed with a pharmaceutically acceptable carrier or diluent.

When the compounds are to be utilized as anorexics, satisfactory resultsare obtained when the compounds are administered at a daily dosage offrom about 10 mg to about 30 mg/kg of animal body weight, preferablygiven in divided doses, e.g., 2 to 4 times a day or in sustained releaseform. For most large mammals the total daily dosage for this use is fromabout 20 mg to about 100 mg and suitable dosage forms comprise fromabout 5 mg to about 50 mg admixed with a pharmaceutically acceptablecarrier or diluent.

A representative formulation suitable for oral administration is atablet prepared by standard tabletting techniques and containing thefollowing:

Parts by Weight 25 inuui'uno The following examples show representativecompounds contemplated by-this invention and the manner in which suchcompounds are prepared. However, it is to be understood that theseexamples are intended for purposes of illustration only and are notintended as in any way limiting the scope of the invention which isdefined in the appended claims.

EXAMPLE 1 l-(p-Chlorophenyl)3-imino-1,5 ,6,1 0b-tetrahydro-3H-oxazolo[4,3-a]isoquinoline Step A. Preparation ofisoquinoline-l-methanol To a flask equipped with a thermometer,condenser, dropping funnel, gas inlet tube and stirrer is added 500 ml.of absolute tetrahydrofuran and 26.0 g. (0.10 mole) a-(p-chlorophenyl)-of l-cyano-2-benzoyl-l,2-dihydroisoquinoline. The system is blanketedwith nitrogen and the solution cooled in an ice-salt-methanol bath to aninternal temperature of l5C. To the cooled solution is then added,dropwise over a period of 15 minutes, 50 ml. of a 2 M solution ofphenyllithium in tetrahydrofuran. To the resulting solution is added,with stirring, a solution of 14.1 g. (0.10 mole) of p-chlorobenzaldehydein ml. of tetrahydrofuran at such a rate that the internal temperaturedoes not exceed 10C. After the addition is completed the solution isstirred for an additional hour at 10C. and then allowed to stand at roomtemperature (2025C.) for 12 hours. To the solution is then added 500 ml.of tetrahydrofuran and the resulting solution extracted first with 30m1. of water, then with 30 m1. of 0.5 N hydrochloric acid and then againwith 30 ml. of water. The tetrahydrofuran is then removed in vacuo andthe residue [benzoate salt of a-(pchlorophenyl)-isoquinoline-1methanol]dissolved in 500 ml. of percent ethanol. To the resulting solution isadded 16.2 g. (0.29 mole) of potassium hydroxide in ml. of water. Theresulting mixture is refluxed for 16 hours and then concentrated invacuo. To the residue is added 100 ml. of water and the resultingsolution extracted with 200 ml. of toluene. The toluene extract is driedover anhydrous magnesium sulfate and the toluene then removed in vacuoto obtain a-( pchlorophenyl)-isoquinoline-1methanol, m p. v98"10 3C.

When the above procedure designated Step A is carried out andm-trifluoromethyl benzaldehyde, pfluorobenzaldehyde or3,4-dichlorobenzaldehyde is used in place of p-chlorobenzaldehyde, thereis obtained a-(m-trifluoromethylphenyl)-isoquinoline-1- methanol (m.p.9799C), a-(p-fluorophenyly isoquinoline-l-methanol (m.p. 85-87C), ora-(3,4- dichlorophenyl )-isoquinoline-l -metha.nol (m.p. l l41 16C),respectively.

Step B. Preparation of a-(p-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-l methanol A mixture of 14.0 g. (0.052 mole) ofa-(pchlorophenyl)-isoquinoline-l-methanol, 100 ml. of acetic acid and0.5 g. of platinum dioxide (ina Paar hydrogenation bottle) ishydrogenated at 45 psi. and room temperature until the hydrogen uptakeis complete (3 equivalents hydrogen; 3 hours). The catalyst is thenfiltered of? and the filtrate concentrated in vacuo. To the resultingoily residue is added 75 ml. of 2N sodium hydroxide and the resultingmixture extracted with ml. of chloroform. The chloroform extract isdried over anhydrous magnesium sulfate and then concentrated in vacuo.The resulting residue is crystallized from pentane to obtaina-(p-chlorophenyl)-l,2,3,4- tetrahydroisoquinoline- 1 methanol, m.p,97-101C.

When the procedure of Step B is used and a-(mtrifluoromethylphenyl)-isoquinoline- 1 -methanol, a-( pfluorophenyl)-isoquinoline-l-methanol,or a-(3,4- dichlorophenyl)-isoquinoline-l-methanol is used in place ofa-(p-chlorophenyl)-isoquinoline-l-methanol, there is obtaineda-(m-trifluoromethylphenyl)-1,2,3,4- tetrahydroisoquinoline- 1 methanol(m.p. 97.5 -99.5) a-(p-fluorophenyD-l ,2,3 ,4-tetrahydroisoquinolinelmethanol (m.p. 7378C), or a-(3,4-dichlorophenyl) 1,2,3,4-tetrahydroisoquinoline-1 methanol (m.p. 8999C), respectively.

Step C. Preparation of 1-(p-chlorophenyl)-3imino- 1,5 ,6, 1Ob-tetrahydro-3H-oxazolo[4,3-a]isoquinoline A solution of 7.3 g. (0.027mole) of a-(pchlorophenyl)-l ,2,3,4-tetrahydroisoquinoline-lmethanol,4.4 g. (0.0534 mole) of sodium acetate and 125 ml. of methanol is cooledto about C. To the cooled solution is added, dropwise, a solution of 2.8g. (0.0267 mole) of cyanogen bromide in ml. of methanol. After stirringfor 12 hours at room temperature (25C.) the solvent is evaporated andthe residue dissolved in water. To the resulting solution is added 2Nsodium hydroxide until basic (pl-l 10). The resulting oil is extractedwith 75 ml. of methylene chloride, the methylene chloride extract driedover anhydrous magnesium sulfate and then concentrated in vacuo toobtain l-( p-chlorophenyl )-3-imino-l ,5,6, l Ob-tetrahydro-3H-oxazolo[4,3-a1isoquinoline as an oil (lsomer A).

The oily base is dissolved in tetrahydrofuran, the resulting solutiontreated with hydrogen chloride gas and precipitated salt recovered byfiltration to obtain l-( pchlorophenyl)-3-imino-l ,5 ,6, lOb-tetrahydro-SH- oxazolo[4,3-a}isoquinoline hydrochloride, m.p. 160-l68C. (lsomer A). When the above oily base dissolved in tetrahydrofuranis treated with maleic acid, there is obtained1-(p-chlorophenyl)-3-imino-l ,5,6, 10btetrahydro-3H-oxazolo[4,3-a1isoquinoline maleate; m.p. l68-l69C(lsomer A).

When the above procedure designated Step C is repeated anda-(m-trifluoromethylphenyl)-1,2,3,4- tetrahydroisoquinolinel -meth anol,a-( pfluorophenyl)-1,2,3,4-tetrahydroisoquinoline-lmethanol, ora-(3,4-dichlorophenyl)-l,2,3,4l-tetrahydroisoquinoline-l-methanol isused in place of a-(pchlorophenyl l ,2,3 ,4-tetrahydroisoquinoline-1methanol, there is obtained l-( mtrifluoromethylphenyl )-3-imino-l ,5,6, l Ob-tetrahydro- 3H-oxazolo[4,3-ajisoquinoline hydrochloride (m.p.l- 86l90C.) (lsomer A), l-(p-fluorophenyl)-3-iminol,5,6, l0b-tetrahydro-3H-oxazolo[ 4,3-alisoquinoline hydrochloride (m.p.227230C.) (lsomer A), or 1- (3,4-dichlorophenyl)-3-imino-l ,5 ,6, lOb-tetrahydro- 3H-oxazolo[4,3-a]isoquinoline hydrochloride (m.p. l-68l70C.) (lsomer A), respectively.

Likewise, when the above procedure designated Step C is used and7-methyl-a-phenyl-l,2,3,4-tetrahydroisoquinoline-l-methanol, V7-chloro-a-phenyll,2,3,4-tetrahydroisoquinoline-l-methanol, or 7-fluoro-a-phenyl-l ,2,3 ,4-tetrahydroisoquinolinel methanol is used inplace of a-(p-chlorophenyD- l ,2,3 ,4-tetrahydroisoquinolinel -methanol,there is obtained l-phenyl-3 -imino-9-methyl-1 ,5 ,6,10btetrahydro-3H-oxazolo[4,3-a]isoquinoline hydrochloride (m.p.267-269C.) (lsomer A), l-phenyl-3-imino- 9-chlorol ,5 ,6, l0b-tetrahydro-3H-oxazolo[4,3- a]isoquinoline hydrochloride (m.p.26l262C.) (lsomer A), or1-phenyl-3-imino-9-fluoro-l,5,6,l0btetrahydro-3H-oxazolo[4,3-a1isoquinolinehydrochloride (m.p. 258-259C.) (lsomer A), respectively.

EXAMPLE 2 1-(p-Chlorophenyl)-3-imino-l ,5,6, l 0b-tetrahydro-3H-oxazolo[ 4,3-a]isoquinoline hydrochloride (Alternate process) Step A.Preparation of l-(p'chloro-a-hydroxybenzyl)- l ,2,3,4-tetrahydroisoquinoline-2-carboxamide To a solution of 5.6 g. ofa-(p-chlorophenyD-l,2,3,4- tetrahydroisoquinoline-l-methanol in 12 ml.of methanol and 3.5 ml. of concentrated hydrochloric acid is added asolution of 1.8 g. of potassium isocyanate in 4 ml. of water. Theresulting mixture is stirred overnight (16 hours) at room temperature(2025C.) and the resulting solid mass diluted with 10 ml. of methanoland 10 ml. of water and then recovered by filtration to obtain l-(p-chloro-a-hydroxy benzyl )-l ,2 ,3 ,4-tetrahydroisoquinoline-2-carboxamide, m.p. 6769C. Step B. Preparation ofl-(p-chlorophenyl)-3-iminol ,5 ,6, l0b-tetrahydro-3H-oxazolo[4,3-a]isoquinoline hydrochloride To a cooledsolution (ice bath) of 12.5 g. of l(pchloro-a-hydroxybenzyD-l ,2,3 ,4-tetrahydroisoquinoline-2-carboxamide in 200 mL, of methylene chloride isadded, with stirring, a solution of 5.0 g. of thionyl chloride in 40 ml.of methylene chloride. The resulting solution is refluxed for 30 minutesand then evaporated in vacuo. The residue is heated with ml. of water ona steam bath for 30 minutes, then cooled and the resulting solidmaterial recovered by filtration and crystallized from methylenechlorideacetone (1:!) to obtainl-(p-chlorophenyl)-3-iminol,5,6,10b-tetrahydro-3H-oxazolo[4,3-a1isoquinolinehydrochloride, m.p. 239240C. (dec.) (lsomer B).

When the procedure of Steps A and B immediately above are used anda-(m-trifluoromethylphenyl)- 1,2,3,4-tetrahydroisoquinolinel -methanol,a-(pfluorophenyl)- l ,2,3 ,4-tetrahydroisoquinolinel methanol, ora-(3,4-dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline-lmethanol is usedin place of a-(pchlorophenyl)- l ,2,3,4-tetrahydroisoquinoline- 1methanol, there is obtained 1 -(mtrifluoromethylphenyl )-3-imino-l ,5,6,l Ob-tetrahydro- 3H-oxazolo[4,3-ajisoquinoline hydrochloride (m.p. 2-44-245C.) (lsomer B), l-(p-fluorophenyl)-3-iminol ,5 ,6, 10b-tetrahydro-3H-oxazolo[4,3-a1isoquinoline hydrochloride (m.p.209-2l1C.) (lsomer B), or 1- (3 ,4-dichlorophenyl)-3-imino-l ,5 ,6, 1Ob-tetrahydro- 3H-oxazolo[4,3-a1isoquinoline hydrochloride (m.p. 2-l9-22lC.) (lsomer B), respectively.

EXAMPLE 3 l-Phenyl-3-imino-l ,5,6, 1 0b-tetrahydro-3H-oxazolo[4,3-a]isoquinoline A solution of 12.5 g. (0.052 mole) ofa-phenyll,2,3,4-tetrahydroisoquinoline-l-methanol, 8.5 g. (0.104 mole)of sodium acetate and 100 ml. of methanol is cooled to about 5C. To thecooled solution is added, dropwise, a solution of 5.5 g. (0.052 mole) ofcyanogen bromide in 25 ml. of methanol. After stirring for 12 hours atroom temperature (20-25C.) the solvent is evaporated and the residuedissolved in water. To the resulting solution is added 2N sodiumhydroxide until basic (pH 10). The resulting oil is extracted with 100ml. of methylene chloride, the methylene chloride extract dried overanhydrous magnesium sulfate and then concentrated in vacuo to obtainl-phenyl-3- 9 imino-l ,5,6, lb-tetrahydro 3H-oxazolo[4,3- a]isoquinolineas an oil (Isomer A).

The oily base is dissolved in tetrahydrofuran, the resulting solutiontreated with hydrogen chloride gas and the precipitated salt recoveredby filtration to obtain 1- phenyl-3-iminol ,5,6,10b-tetrahydro-3l-l-oxazolo[4,3- alisoquinoline hydrochloride, m.p.228230C. (Isomer A).

EXAMPLE 4 l-(2,4-dichlorophenyl)-3-imino-1,5 ,6,l0b-tetrahydro-3H-oxazolo[4,3-a]isoquinoline Step A. Preparation ofa-(2,4-dichlorophenyl)- isoquinolinel methanol To a flask equipped witha thermometer, condenser, dropping funnel, gas inlet tube and stirrer isadded 650 ml. of absolute tetrahydrofuran and 65 g. (0.25 mole) ofl-cyano-Z-benzoyl-l ,2-dihydro-isoquinoline. The system is blanketedwith nitrogen and the solution cooled in an ice-salt-mathanol bath to aninternal temperature of 15C. To the cooled solution is then added,dropwise over a period of 15 minutes, 125 ml. (0.25 mole) of 2.14 molarphenyllithium in tetrahydrofuran. To the resulting solution is added,with stirring, a solution or 43.8 g. (0.25 mole) of 2,4-dichlorobenzaldehyde in 300 ml. of tetrahydrofuran at such a rate thatthe internal temperature does not exceed lOC. After the addition iscompleted the solution is stirred for an additional hour at lOC. andthen allowed to stand at room temperature (20-25C.) for 12 hours. To thesolution is then added 500 ml. of tetrahydrofuran and the resultingsolution extracted first with 75 ml. of water, then with 75 ml. of 0.5 Nhydrochloric acid and then again with 75 ml. of water. Thetetrahydrofuran is then removed in vacuo and the residue dissolved in1,000 ml. of 95 percent ethanol. To the resulting solution is added 40.5g. (0.725 mole) of potassium hydroxide in 250 ml. of water. Theresulting mixture is refluxed for 16 hours and then concentrated invacuo. To the residue is added 250 ml. of water and the resultingsolution extracted three times each with 200 ml. of toluene. The tolueneextract is dried over so dium sulfate, the toluene then removed in vacuoand the residue crystallized from ether-pentane 1:1 to obtaina-(2,4-dichlorophenyl)-isoquinoline-lmethanol, m.p. 97-l00C. Step B.Preparation of a-(2,4'dichlorophenyl)-l ,2,3,4- tetrahydroisoquinolinelmethanol A mixture of 40.9 g. (0.135 mole) of 1(3,4-dichlorophenyl)isoquinoline-lmethanol, 125 ml. of acetic acid and 1.0 g.of platinum dioxide (in a Paar hydrogenation bottle) is hydrogenated at49 p.s.i. and room temperature until the hydrogen uptake is complete (4hours). The catalyst is then filtered off and the filtrate concentratedin vacuo. To the resulting oily re sidue is added ml. of 2N sodiumhydroxide and the resulting mixture extracted with 250 ml. ofchloroform. The chloroform extract is dried over anhydrous sodiumsulfate and then concentrated in vacuo. The resulting residue iscrystallized from pentane-ether (1:1) to obtaina-(2,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolinel methanol, m.p. l32l 34C.

Step C. Preparation of 1-(2,4-dichlorophenyl)-3- imino-l,5,6,10b-tetrahydro-3H-oxazolo[4,3- alisoquinoline A solution of 20.0 g.(0.065 mole) of (2-(2,4- dichlorophenyl)-l ,2,3,4-tetrahydroisoquinolinel methanol, 10.7 g. (0.13 mole) of sodiumacetate and 500 ml. of methanol is cooled to about 5C. To the cooledsolution is added, dropwise, a solution of 6.8 g. (0.065 mole) ofcyanogen bromide in 50 ml. of methanol. After stirring for 15 hours atroom temperature (2025C.) the solvent is evaporated'and the residuedissolved in water. To the resulting solution is added 2N sodiumhydroxide until basic (pH 10). The resulting oil is extracted with ml.of methylene chloride, the methylene chloride extract dried overanhydrous magnesium sulfate and then concentrated in vacuo to obtain1-(2,4-dichlorophenyl)-3'imino-l ,5,6, 10btetrahydro-3H-oxazolo[4,3-a1isoquinoline as an oil (lsomer A).

The oily base is dissolved in tetrahydrofuran, the resulting solutiontreated with hydrogen chloride gas and precipitated salt recovered byfiltration to obtain 1- (2,4-dichlorophenyl)-3-imino-l ,5,6,10b-tetrahydro* 3l-l-oxazolo[4,3-a]isoquinoline hydrochloride, m.p.17- 0-l76C. (lsomer A).

EXAMPLE 5 l-( 2,4-dichlorophenyl)-3-imino-1 ,5 ,6, l Ob-tetrahydro-3H-oxazolo[4,3-a]isoquinoline hydrochloride (Alternate process) Step A.Preparation of 1-( 2 ,4-dichloro-ahydroxybenzyl )-l ,2,3,4-tetrahydroisoquinoline-2- carboxamide To a solution of 7.2 g. (0.021mole) of a-(2,4- dichlorophenyl)-l,2,3,4-tetrahydroisoquinoline-1-methanol in 50 m1. of methanol, 200 ml. of water, and 2.2 ml. ofconcentrated hydrochloric acid is added a solution of 2.0 g. ofpotassium isocyanate in 10 ml. of water. The resulting mixture isstirred for 48 hours at room temperature (2025C.) and the resultingsolid mass recovered by filtration to obtainl-(2,4-dichloroa-hydroxybenzyl )-l ,2,3 ,4-tetrahydroisoquinoline-2'carboxamide. Step B. Preparation of l-(2,4-dichlorophenyl)-3-irnino 1 ,5,6, l 0b-tetrahydro-3H-oxazolo[4,3-a]isoquinoline hydrochloride To acooled solution (ice bath) of 6.2 g. (0.018 mole) ofl(2,4-dichloro-a-hydroxybenzyl l ,2,3 ,4-tetrahydroisoquinoline-Zcarboxamide in 150 ml. of methylene chloride isadded, with stirring, a solution of 2.2 g. of thionyl chloride in 10 ml.of methylene chloride. The resulting solution is refluxed for 30 minutesand then evaporated in vacuo. The residue is heated with 50 ml. of wateron a steam bath for 30 minutes, then cooled and the resulting solidmaterial recovered to obtainl-(2,4-dichlorophenyl)-3imino-l,5,6,10btetrahydro-3H-oxazolo[4,3-alisoquinolinehydrochloride, m.p. l96-l99C. (lsomer B).

EXAMPLE 6 iphenyl-3imino-S-methyl-1 ,5 ,6, 1b-tetrahydro-3I-loxazolo[4,3-a1isoquinoline hydrochloride Step A.Z-benzoyl-l ,2-dihydro-3-methylisoquinolinel carbonitrile In a 3-literfour-neck flask, equipped with mechanical stirrer, dropping funnel,thermometer and condenser are placed a solution of 196 g. of potassiumcyanide in 1,250 ml. of water and 143 g. of 3- methylisoquinoline. Whilethe temperature was maintained between 5 and by use of an ice bath, 281g. of benzoylchloride is added dropwise for 2 hours. After another 1.5hours, the resulting material crystalizes and is filtered off, washedwith water (200 ml), 2N HCl solution (300 ml) and water (300 ml). Thecrude material (330 g.) is recrystallized from ethanol three times toafford Z-benzoyl-l,2-dihydro-3methylisoquinolinel-carbonitrile; m.p.137138C.

Step B. a-phenyl-S-methyl-l,2,3,4-tetrahydroisoquinoline-l methanolhydrochloride 2-benzoyll ,2-dihydro-3methylisoquinoline (27.4 g.) isdissolved in 500 ml. of absolute tetrahydrofuran in a 2-liter four-neckflask equipped with thermometer, dropping funnel, condenser withnitrogen inlet and mechanical stirrer. The internal temperature ismaintained between C. and 10C. A 2 molar solution (50 ml) ofphenyllithium in benzene/ether (70:30) is added dropwise."l"o theresultant red solution, 10.6 g. of benzaldehyde in 75 ml. absolutetetrahydrofuran is added dropwise over a 20 minute period. The mixtureis stirred for 1 hour at 10C, then at room temperature overnight. Afterwork up 38 g. of an oil is obtained which is hydrolized in 100 ml. of 2Npotassium hydroxide and 500 ml. of ethanol by refluxing overnight. Themixture is concentrated in vacuo to about 200 m1. and worked up toprovide 28 g. of an oil which is hydrogenated without furtherpurification in 90 ml. of glacial acetic acid in the presence of 250 mg.of platinum dioxide. After the absorption of hydrogen has stopped, thecatalyst is removed by filtration and the solution is evaporated invacuo. Ether (100 ml) is added and the prodnot is precipitated ashydrochloride by adding 100 ml. of 2N HC] solution. Crude product (16.2g.) is filtered off and recrystallized from ethanol/ether to yield 13.8g. of a-phenyl-3-methyl-l,2,3,4-tetrahydroisoquinoline-1 methanolhydrochloride; m.p. 198-199C.

When the procedure of Steps A and B above are repeated andp-chlorobenzoylchloride or 3,4- dichlorobenzoylchloride is used in placeof benzoylchloride, there is obtained a-(p-chlorophenyl)-3- methyl-1,2,3 ,4-tetrahydroisoquinoline-l methanol hydrochloride; (mp. 213C), ora-(3,4-dichlorophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-lmethanol hydrochloride;(rn.p.230233C), respectively. Step C. l-(a-hydroxybenzyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-Zcarbonitrile a-phenyl-3-methyl-1,2,3,4-tetrahydroisoquinolinel methanol HCl (4.5 g.) is dissolved in 100ml. of warm water. 10 ml. of 2N sodium hydroxide solution andmethylenechloride are added and work up yields 3.2 g. ofoz-phenyI-3-methyi-l,2,3,4-tetrahydroisoquinoline- Lmethanol; m.p.9698C. To 2.53 g. of the above free base dissolved in 70 ml. of absolutemethanol is added 1 g. of anhydrous sodium acetate. To this ice coldsolution is added, dropwise, 1.1 g. of cyanogen bromide in 30 ml. ofabsolute methanol. After 2 hours at room temperature, methanol isevaporated in vacuo. Extraction with methylene chloride afi'ords 3.8 g.of crude product; mp. 141C. After recrystallization from methylenechloride/hexane 2.5 g. of pure l-(ahydroxybenzyl )-3-methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonitrile is obtained;

(m.p. 144-145C).

When the above process is carried out and a-(p' chlorophenyl)-3-methyl-l,2,3,4-tetrahydroisoquinoline-l-methanol ora-(3,4-dichlorophenyl)-3-methyll,2,3,4-tetrahydroisoquinoline-lmethanolis used in place of a-phenyl-3-rnethyll ,2,3,4-tetrahydroisoquinoline-lmethanol, there is obtainedl-(pchloro-a-hydroxybenzyl)-3 methyl-l ,2,3 ,4-tetrahydroisoquinoline-Z-carbonitrile (mp 151C) orl(3,4-dichloro-a-hydroxybenzyl)-3-methyl-1 ,2,3,4-tetrahydroisoquin'oline-Z-carbonitrile "'(m.p.

. l47149C), respectively.

Step D. l-phenyl-3 -imino-5 methyl-l ,5 ,6,10btetrahydro-3H-oxazolo[4,3-a]isoquinoline hydrochloride.

1-( a-hydroxybenzyl )-3-methyl-l ,2,3 ,4-tetrahydroisoquinoline-Z-carbonitrile 1.5 g.) is cyclized at 25C. with10 ml. ofN HCl in ethanol. The hycrochloride precipitates and isfiltered to provide 1.8 g. of crude material; mp. 252C. Tworecrystallizations from ethanol/ether (1:1) provides 1-phenyl3-imino-5-methyl-l ,5 ,6 l 0b-tetrahydro-3H-oxazolo[ 4,3- alisoquinolinehydrochloride; m.p. 267268C.

When the process of Step D is repeated and 1-(pchloro-a-hydroxybenzyD-3methyl-1 ,2,3,4-tetrahydroisoquinoline-Zcarbonitrile or dichloro-a-hydroxybenzyl)-3-methy1-l ,2,3,4- tetrahydroiso-quinoline-Z-carbonitrile is used inplace of 1-( a-hydroxybenzyD-3 rnethyl-l ,2,3 ,4-tetrahydroisoquinoline-2-carbonitrile, and when in the case of thep-chloro compound HBr is used in place of HCl, there is obtained1p-chlorophenyl-3-imino-5 methyl-1,5 ,6, 10b-tetrahydro3H-oxazolo{ 4,3alisoquinoline hydrobromide (m.p. 237238C) or 1- (3 ,4-dichlorophenyl)-3 -imino 5 methyl-l ,5 ,6, l Ob-tetrahydro-3H-oxazolo[4,3-a1isoquinoline hydrochloride (m.p. 246247C), respectively.

EXAMPLE 7 7-chloro-a-phenyl-l ,2,3 ,4-tetrahydroisoquinoline- 1 methanolStep A. 1benzyl-7-chloro-3,4-dihydroisoquinolineN'(p-chlorophenethyl)-2-phenyl acetamide (57 g.) is refluxed overnightin 500 m1. of xylene in the presence of 120 g. of phosphorous pentoxideand g. of pumice. The xylene layer is decanted and the residue dissolvedin water, ice and concentrated HCl. The pumice is filtered off and theaqueous solution extracted with dichloromethane. The organic phase isdiscarded and the aqueous part is made basic (pH with 50% NaOH andextracted 3 times with dichloromethane. The solvent is evaporatedproviding 23 g. of crude 1- benzyl-7 -chloro-3 ,4-dihydroisoquinoline.Step B. 1-benzoyl-7-chloro-3,4-dihydroisoquinoline A solution of1-benzyl-7-chloro-3 ,4- dihydroisoquinoline (22 g.) in 500 ml. ofbenzene is treated by bubbling air through the solution, and evaporatingit to dryness, to obtain 6.2 g. of brown oil. After purification onsilica gel, 550 mg. of crystalline 1-benzoyl-7-chloro-3,4-dihydroisoquinoline is obtained (m.p. 9899C). StepC. 7-chloro-a-phenyl-1,2,3,4-tetrahydroisoquinoline- 1 -methanoll-Benzoyl-7-chloro-3,4-dihydroisoquinoline (2.0 g)

dissolved in 50 ml. of absolute ethanol is hydrogenated at about 40 psi.in the presence of 500 mg. of platinum dioxide. After one-half hour,hydrogen absorption ceases, the catalyst is filtered off, and thesolvent is evaporated, leaving 1.3 g. of crude 7-chloro-a-phenyl-1,2,3,4-tetrahydro-isoquinoline-l-methanol as an oil.

When Steps A, B and C immediately above are repeated usingN-(p-methylphenethyl)-2-phenyl acetamide orN-(p-fluorophenethyl)-2-phenyl acetamide in place ofN-(pchlorophenethyl)-2-phenyl acetamide, there is obtained7-methyl-a-phenyl-1,2,3,4-tetrahydroisoquinoline-l-methanol (m.p.101.1-2C) or 7- fluoro-a-phenyl-l ,2,3,4-tetrahydroisoquinoline-1-methanol, respectively.

What is claimed is:

l. A c mpound of the formula where R, R, R and R, independently,represent hydrogen, trifluoromethyl, or halo having an atomic weight ofabout 19-36;

R and R independently, represent hydrogen, straight chain lower alkyl,or halo having an atomic weight of about 19-36; and

Alk represents straight chain lower alkyl,

provided

2. R, R1, R2 and R3 are such that there is never a trifluoromethyl groupon each of two adjacent carbon atoms.
 2. The compound according to claim1 which is 1-( Alpha-hydroxybenzyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonitrile.3. The compound according to claim 1 which is 1-(p-chloro- Alpha-hydroxybenzyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonitrile.4. The compound according to claim 1 which is 1-(3,4-dichloro-Alpha-hydroxybenzyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonitrile.